ABSTRACT Bone is a highly dynamic organ that undergoes continuous remodeling and maintains a balance between bone formation and resorption. Bone cells, osteoblasts, which contribute to new bone formation, and osteoclasts, which resorb bone tissue, act in concert to maintain bone homeostasis. A perturbation to these highly coordinated cellular activities often results in bone metabolic and degenerative diseases such as osteoporosis. Osteoporosis is a disease of dysregulated bone homeostasis characterized by low bone mass and a significant increase in fracture risk. This pathological condition represents a major public health problem with osteoporosis-associated fractures occurring in an estimated one in two women and one in four men age 50 and older in the United States alone. We recently showed adenosine A2B receptor (ADORA2B), a G-protein coupled receptor on the cell membrane, plays an important role during osteogenic and osteoclastic differentiation of MSCs and macrophages respectively. These findings along with our ongoing studies highlight the potential of ADORA2B as a novel therapeutic target for the treatment of diseases characterized by low bone mass such as osteoporosis. Unlike most of the currently available drugs that only slow down disease progression but do not promote bone formation, activation of ADORA2B offers a therapy with dual function that promotes osteoblast differentiation (bone formation) while inhibiting osteoclast activity (bone resorption). By employing a number of in vitro and in vivo models, we will: (1) study the role of ADORA2B on osteoblast and osteoclast differentiation and unearth the underlying intracellular signaling mechanism, (2) determine the therapeutic potential of targeting ADORA2B to treat postmenopausal osteoporosis by using an ovariectomized mouse model, and (3) establish humanized osteoporotic bone in animal models. Targeting ADORA2B to treat bone loss is not limited to the study of osteoporosis but has broad applications that can be extended to treatment of various bone metabolic diseases. The humanized bone tissue models could lead to new enabling technologies for drug discovery and overcome species-specific discrepant findings in preclinical studies.